Sulfonamides crystalluria

The short-acting sulfonamides include sulfadimidine, sulfamerazine and sulfathiazole. Sulfadimidine, as the most important representative of this group, is relatively soluble and has therefore a lower risk of causing crystalluria while sulfamerazine and sulfathiazole are less soluble sulfonamides. Sulfadimidine has good oral absorption. It has an elimination half-life between 1.5 and 5 hours, depending on acetylator phenotype. 

Sulfonamides, such as sulfadiazine, in combination with pyrimethamine, are considered the treatment of choice of symptomatic toxoplasmosis. Patients should be well hydrated to prevent crystalluria this problem may be reduced with the use of triple sulfas (trisulfapyrimidine). Some regimens have included a sulfonamide (sul-fadoxine) in combination with pyrimethamine (Fansidar) for the treatment of chloroquine-resistant malaria caused by P. falciparum. 

If the concentration of the sulfonamide is sufficiently high and its aqueous solubility is sufficiently low, the free drug or its metabolites may form crystals and cause bleeding or complete obstruction of the kidneys. Combinations of sulfa compounds have been developed for the purpose of lowering the dosage of individual components to reduce the chance of crystalluria (e.g., triple sulfas, such as the trisulfapyrimidines). 

Sulfonamides also cause renal irritation and may precipitate renal colic. Crystalluria, haematuria and albuminuria can also occur which may lead to the development of oliguria and anuria. 

Sulfonamides may precipitate in urine, especially at neutral or acid pH, producing crystalluria, hematuria, or even obstruction. This is rarely a problem with the more soluble sulfonamides (eg, sulfisoxazole). Sulfadiazine when given in large doses, particularly if fluid intake is poor, can cause crystalluria. Crystalluria is treated by administration of sodium bicarbonate to alkalinize the urine and fluids to maintain adequate hydration. Sulfonamides have also been implicated in various types of nephrosis and in allergic nephritis. 

As was true for the sulfonamides, the risk of crystalluria due to penicillins is increased by high doses, a low urinary pH, and low urine output. 

The frequency and severity of the adverse effects of sulfonamides correspond to those seen with other antibacterial agents (2-5%). Dose-related effects, which tend to be more troublesome than serious, include gastrointestinal symptoms, headache, and drowsiness. Crystalluria can occur, but urinary obstruction is rare. Hematological adverse effects due to folic acid antagonism occur primarily in combination with trimethoprim. Hemolytic anemia occurs in patients with enzyme deficiencies and abnormal hemoglobins. Hypersensitivity... 

Renal complications that occur in relation to sulfonamide administration include crystalluria, tubular necrosis, interstitial nephritis, and glomerular lesions as part of a vasculitis syndrome. 

Weinstein L, Madoff MA, Samet CM. The sulfonamides. The New England journal of medicine. 1960 Nov 3 263 900-7 contd. Dorfman LE, Smith JP. Sulfonamide crystalluria a forgotten disease. The Journal of urology. 1970 Sep 104(3) 482-3. 

The treatment of choice for coccidiosis is the sulfonamide antimicrobial agents (see Ch. 2). The sulfonamides disrupt folic acid and nicotinamide metabolism and coenzymes I and II by competing with para-aminobenzoic acid (PABA). Coccidia must manufacture their own folic acid and, therefore, this step is mandatory in the pyrimidine pathway of these parasites. Sulfamethazine (sulfadimidine) at 220mg/kg i.v. or orally, or sul-fadimethoxine (55mg/kg) orally or sulfathiazole (66mg/kg) orally, all once daily for 5-7 days, are used commonly for the treatment of equine coccidiosis. The signs of toxicity of the sulfonamides are covered extensively in Chapter 2. Crystalluria,... 

Side effects Headaches, fatigue, drowsiness, nausea, heartburn, vomiting, diarrhea. Vitamin C with aspirin or sulfonamides may cause crystal formation in the urine (crystalluria) and can also cause a false negative occult (blood) stool result and false positive sugar result in the urine when tested by the Clinitest method. 

Renal stone formation, possibly also accompanied by intratubular precipitation of crystalline material, has been arare complication of drug therapy. Until the AIDS era, triamterene had been the drug most frequently associated with renal stone formation, with an incidence approximating 1 in 1500 users of triamterene-hydrochlorothiazide. However, it has been unclear whether triamterene or its metabolites actually initiated stone formation, or are passively absorbed onto the organic matrix of pre-existing calculi. Sulfadiazine is a poorly soluble sulfonamide that has caused symptomatic acetylsul-fadiazine crystalluria with stone formation and flank or back pain, hematuria, or renal insufficiency in up to 29% of patients treated with the drug. A high urine volume and urinary aUcalinization to... 

The potential for formation of urinary tract crystalluria and calculi in humans can be readily assessed in the clinical setting (McPherson et al. 2006 Pearle and Lotan 2007). This can be accomplished by routine collection of urine for urinalysis, including sediment analysis for crystals, cells, and casts. As indicated above, the presence of abnormal crystals or an increase in crystals is not sufficient to indicate urothelial toxicity in humans. It is only the presence of calculi that poses any potential for urinary toxicity. Since calculi will frequently be associated with obstruction and consequent pain, this will be a cUnical observation that is readily made by the patient with corroboration by the clinician. Many substances that can lead to the production of calculi in rodents do not appear to do so in humans. Thus, sulfonamides can produce crystallmia and calculi frequently in rodents, whereas sulfonamide crystalluria is common in humans but calculi are rare (McPherson et al. 2006 Pearle and Lotan 2007). Another example is muraglitazar (Dominick et al. 2006), which leads to formation of a variety of urinary solids in rats, including calculi, but it is not associated with the formation of urinary crystalluria or calculi in humans. 

Sulfonamide-related effects are described above, although crystalluria and drug interactions are not common with TMP-SMX. 

These compounds were extensively used in the 40 s through the 60 s to treat pulmonary and other systemic infections. Reports of acute renal failure, most secondary to crystalluria were common [1-3]. Rarely, the sulfonamides can cause acute interstitial nephritis, necrotizing arteritis or hemoglobinuric acute renal failure due to massive acute hemolytic anemia [4, 6]. 

Dorfman LE, Smith JR Sulfonamide crystalluria A forgotten disease. J Urol 1970 104 482-483. 

Fewer than 0.1% of patients receiving sulhsoxazole suffer serious toxic reactions. The untoward effects prodnced by this agent are similar to those that follow the administration of other sulfonamides. Because of its relatively high solubility in the urine as compared with sulfadiazine, sulhsoxazole only infrequently produces hematuria or crystalluria (0.2 to 0.3%). Despite this, patients taking this drug should ingest an adequate quantity of water. Sulhsoxazole and all snlfonamides that are absorbed must be used with caution in patients with impaired renal function. Like all sulfonamides, sulhsoxazole may produce hypersensitivity reactions, some of which are potentially lethal. Sulhsoxazole currently is preferred over other snlfonamides by most clinicians when a rapidly absorbed and rapidly exaeted sulfonamide is indicated. 

Like all sulfonamides, sulfasalazine is contraindicated in patients with known hypersensitivity to other drags containing sulfur (thiazides, furosemide, or oral sulfonylureas), in patients with known hypersensitivity to salicylates, in patients with severe renal or hepatic dysfunction, or porphyria, during pregnancy, and during lactation, and in infants and children under age 2. Sulfasalazine is also contraindicated in patients with intestinal or urinary tract obstructions because of the risk of local GI irritation and of crystalluria. 

Concomitant use of urine-acidifying agents (ammonium chloride, ascorbic acid) decreases urine pH and sulfonamide solubility, thus increasing risk of crystalluria. Concomitant use with antibiotics that alter intestinal flora may interfere with conversion of sulfasalazine to sulfapyridine and 5-aminosalicylic acid, decreasing its effectiveness. 

D) Sulfonamide crystalluria is most likely to occur at low urinary pH... 

Megadoses of vitamin C taken with aspirin or sulfonamides may cause crystalluria, crystal formation in the urine. 

The majority of adverse effects to sulfonamides are mild in nature and reversible, although idiosyncratic drug reactions may occur. Urinary tract disturbances, including sulfonamide crystalluria and hematuria, can be minimized in susceptible animals by maintaining an adequate water intake to maintain a high urine flow. Bone marrow depression and dermatologic reactions have also been associated with sulfonamide therapy in animals. 

Sulfonamide excretion occurs partly via the parent compounds in urine (most readily if urine pH is alkaline, as in herbivores), but predominantly through the less lipid-soluble and therefore more readily excreted metabolites described above. Some sulfonamides are also excreted via the active carrier-mediated transport system, which secretes organic acids from peritubular capillaries across proximal convoluted tubule cells and into tubular lumen fluid. Acetylated sulfonamides are usually less water-soluble than the parent compounds and are the main cause of the crystalluria that can occur, leading to tubular damage. Only small amounts are excreted in bile and milk. 

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